Pharmaceutical compositions containing testosterone and an aromatase inhibitor

ABSTRACT

An implant comprising testosterone or an ester thereof and an aromatase inhibitor; the aromatase inhibitor may be selected from the group consisting of anastrozole, letrozole, and exemestane. In one embodiment the implant is a sustained release, subcutaneous implant. Also disclosed are therapies for patients with symptoms of relative androgen deficiency, breast cancer survivors and other therapies in which testosterone is indicated but elevated estradiol levels are avoided.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.12/620,725, filed Nov. 18, 2009, which claims the benefit of U.S.Application Ser. No. 61/200,867, filed Dec. 5, 2008.

BACKGROUND

Testosterone, delivered by subcutaneous pellet implant has been used inthe United States, Europe and Australia in both men and women to treatsymptoms of testosterone deficiency. Symptoms of testosterone hormonedeficiency include fatigue, lack of energy, depression, memory loss,concentration difficulties, weakness, aches, pains, anemia, suppressedimmune system, insomnia, hot flashes, night sweats, bone loss(osteopenia, osteoporosis), muscle mass loss, inability to loose weight(fat mass), anxiety, emotional lability, vaginal dryness, urinaryurgency, urinary frequency, and incontinence.

Potential benefits of testosterone delivery by implant include increasedbone density, increased energy, relief of lethargy, relief of depressionand anxiety, improved memory and concentration, improved sleep,increased muscle mass, decreased fat mass, relief of aches and pains,relief of breast pain, relief of migraine headaches, restoration of sexdrive and libido, menopausal syndrome relief (hot flashes, nightsweats), prevention of uterine bleeding caused by estrogens, use indysmenorrheic patients with endometriosis or small fibroids, relief ofnocturia and incontinence, relief of vaginal symptoms, arterialvaso-dilation, increased arterial blood flow, lowering the risk ofbreast cancer in women on estrogen/progestin therapy, palliative measure(carcinoma of the breast), decreased proliferation of breast tissue,reduction of ER (estrogen receptor) alpha, enhance immune system, andincreased red blood cell production.

Anastrozole is an aromatase inhibitor and has been used orally as anadjuvant therapy in breast cancer in post-menopausal women. By blockingthe enzyme “aromatase,” anastrozole inhibits the conversion oftestosterone to estradiol thus preventing the stimulation of breasttissue and breast cancer cells by estradiol. Oral anastrozole has beenused in male patients to prevent the conversion of testosterone toestradiol, thus raising testosterone levels and lowering estradiollevels.

SUMMARY OF INVENTION

The invention relates to a pharmaceutical composition comprisingtestosterone or an ester thereof and an aromatase inhibitor. In oneembodiment the pharmaceutical composition is formulated as a sustainedrelease, subcutaneous pellet implant. In this composition, an aromataseinhibitor is combined with testosterone to continuously delivertestosterone and simultaneously prevent the conversion of testosteroneto estradiol by the aromatase inhibitor.

The composition and, more particularly, the testosterone-anastrozolesubcutaneous, sustained release implant, is indicated for use in maleand female patients. It may be used in patients with symptoms ofrelative androgen deficiency (including bone loss, joint/muscular pain,anemia, suppressed immune system, depression, memory loss, fatigue,sexual problems and sleep problems) who may benefit from testosteronetherapy, where elevated estradiol (estrogen) levels are to be avoided.In one embodiment it is indicated for use in breast cancer survivorswhere the use of testosterone has been cautioned against because of thearomatization of testosterone to estradiol, a potent estrogen. Estradiolis known to stimulate proliferation of breast tissue and breast cancer.It may also be indicated for patients with a diagnosis of invasive ornon-invasive breast cancer (e.g., hormone receptor positive (estrogenreceptor positive) breast cancer survivors); patients at high risk forbreast cancer (e.g., family history of breast cancer, gene positive(BRCA I or BRCA II) for breast cancer, prior breast biopsy with ‘atypia’or a diagnosis of ‘atypical ductal hyperplasia,’ or diagnosis of LobularCarcinoma in Situ); patients with benign breast disease (e.g.,fibrocystic breast disease, breast tenderness, cystic mastitis); obesepatients (e.g., elevated aromatase (enzyme) levels are found in fattissue making this group of patients more likely to convert testosteroneto estradiol such that lowering estradiol levels may help with weightloss); male patients on testosterone therapy who have previouslydemonstrated elevated estrogen levels; and patients with insulinresistance (e.g., elevated estrogen has been associated with insulinresistance).

In one embodiment, an implant is composed of the active ingredientstestosterone and anastrozole. In one embodiment the implant may consistof the active ingredients, however, to improve the integrity of thepellet and facilitate its manufacture in one embodiment the activeingredients are used with excipients such as a lubricant and/or abinder. In one embodiment the lubricant is stearic acid. In oneembodiment the binder is povidone. In one embodiment, the excipientsmake up less than 20%, more particularly less than 10%, and still moreparticularly less than 5% of the composition. In one embodiment, theseingredients are formed into an implant such as cylindrical pelletsmeasuring in one case approximately 3.1 mm by 6.5 mm, then packaged andsterilized. In one embodiment the implant contains the testosterone andthe aromatization inhibitor in a weight ratio of about 5:1 to about 30:1and, more particularly in a ratio of about 15:1 to 25:1 and still moreparticularly 10:1 to 20:1. For example in one instance the implantincludes 60 mg testosterone and 6 mg inhibitor and in another instancethe implant contains 60 mg testosterone and 3 mg inhibitor. Preferablythe implant fits through a standard size, 3.2 mm pellet implanter(trocar/cannula) and can be inserted through a small incision intosubcutaneous tissue in an area that experiences relatively littlemovement such as the lower abdomen or upper buttocks. In one embodiment,a single implant may be used. In another embodiment depending on thecondition of the patient, two or more implants may be used together.

In one embodiment, the implant may be formulated to deliver continuous,therapeutic testosterone and anastrozole therapy for 12-16 weeks. In oneembodiment, particularly when the amount of excipients is minimal, theimplant provides approximately zero order release proportional to thesurface area of the pellet(s).

The implant can enable significantly lower dosing (for example, 6 mgreleased over 100 days (0.06 mg/day) vs. 1.0 mg/d oral dose) with fewerside effects than oral anastrozole therapy (see below). In addition,avoiding the GI tract avoids nausea or adverse effects to the GI tract.Subcutaneous delivery also avoids adverse effects from ‘first pass’metabolism in the liver including hepatic-toxicity or increase inclotting factors. Subcutaneous delivery of the combination oftestosterone and anastrozole also can reduce or eliminate patientnon-compliance.

One manifestation of the invention is a subcutaneous, sustained releasepellet implant. However, other dosages such as oral tablets andcapsules, and transdermal patches constitute additional embodiments ofthe invention.

In one embodiment, the combination of testosterone (hormone) withanastrozole (aromatase inhibitor) will elevate testosterone levelswithout elevating or with reduced or limited elevation of estradiollevels.

In one embodiment, the combination of testosterone with anastrozole willrelieve symptoms of hormone deficiency in patients in whom elevatedestrogen levels are contraindicated.

In one embodiment, the combination of subcutaneous testosterone withanastrozole may offer breast protection and reduce the risk of recurrentdisease in breast cancer survivors.

In one embodiment, subcutaneous anastrozole appears to prevent theconversion of DHEA (dehydro-epiandrosterone), an adrenal androgen toestrone, an estrogen that may stimulate breast tissue and elevate withobesity.

DETAILED DESCRIPTION

While testosterone is used in one embodiment of the invention, it willbe understood that esters of testosterone may be used such astestosterone propionate, cypionate, enanthate, decanoate, andundecanoate. Herein, with the exception of the claims, the use of theterm “testosterone” shall be understood to include testosterone and itsesters. The testosterone is used in its crystalline form in oneembodiment but it may be used in its noncrystalline or amorphous form inanother embodiment. The amount of testosterone in the composition, willbe an amount that delivers a pharmaceutically effective serum bloodlevel. In one embodiment, the testosterone is used in implants in anamount of about 30 to 200 mg. In a more particular embodiment, thetestosterone is used in an amount of about 50 to 90 mg. As indicatedearlier, one or more implants may be used depending on the size, weightand condition of the patient.

Representative examples of aromatase inhibitors useful in accordancewith this disclosure include, but are not limited to, anastrozole,letrozole and exemestane. The inhibitor is used in an amount effectiveto prevent formation of the estradiol from the testosterone. The amountis selected to inhibit the aromatase enzyme will depend on the conditionof the patient. More particularly, the inhibitor is used in an amountthat is effective in keeping estradiol blood serum levels less thanabout 54 pg/ml in males and more particularly less than about 45 pg/mland still more particularly less than about 30 pg/ml. In females, theestradiol blood levels are less than 30 pg/ml in one embodiment. Becausethe aromatase inhibitor tends to reside in fat tissue, higher doses maybe desirable in patients who are obese. In one embodiment the implantcontains the inhibitor in an amount of about 1 to 90 mg. In a moreparticular embodiment, the inhibitor may be used in an amount of about 2to 50 mg. and in a still more particular embodiment, the inhibitor maybe used in the implant in an amount of about 3 to 14 mg.

In accordance with one embodiment of the invention an implant isprovided that is able to provide nearly zero order release of thetestosterone. In one embodiment the implant is in excess of 90% or 98%active and contains only a small amount of excipient. In one embodimentthe implant contains a small amount of a pharmaceutically acceptablelubricant (such as stearic acid) sufficient to facilitate removal of theimplant from the pellet forming mold without damage. In anotherembodiment, to improve the structural integrity of the pellet a smallamount of a pharmaceutically acceptable binder is used (e.g., PVP(povidone) (0.2-2 mg) may be used). Neither the stearic acid, norpovidone appears to affect release rate of the active ingredients.

Those skilled in the art will appreciate that the implant can also beformulated as a “matrix” type device, in which an active compound isdispersed in a matrix of carrier material. The carrier material may beeither porous or non-porous, solid or semi-solid, and permeable orimpermeable to the active compound. Matrix devices may be biodegradable,i.e., they may slowly erode after administration. Alternatively, matrixdevices may be nondegradable, and rely on diffusion of the activecompound through the walls or pores of the matrix. Other devices may be“reservoir” type, and consist of a central reservoir of active compoundsurrounded by a rate controlling membrane. The membrane may be porous ornon-porous. The release rate often depends only on the surface area ofthe device. In some cases the sustained release devices are hybrids,having a matrix core surrounded by a membrane.

A number of implant devices are known in the art that may be adopted foruse in accordance with this disclosure. For example:

H. Nash, et al., “Steroid Release From Silastic Capsules and Rods”Contraception, 18, 367-394 (1978) discloses both reservoir and matriximplants fashioned from Silastic®, polydimethylsiloxane, for sustainedadministration of contraceptive steroids. The steroids used aretestosterone and testosterone propionate.

Shippy, et al., “Controlled Release of Testosterone Using SiliconeRubber” J. Biomed. Mater. Res., 7, 95-110 (1973) discloses a reservoirdevice comprising a crystalline testosterone cylinder dipped inSilastic® or a Silastic®/testosterone suspension.

Japanese application J5 9044-310A to Nippon Kayaku discloses a matrixdevice of a silicone rubber formulation containing a crystallinepowdered dissolution assistant (especially a monobasic amino acid, e.g.,glycine or alanine, NaCl or mannitol) and an antibiotic or anticancerdrug. These devices are reported to achieve a release time of one weekto one month.

UK Patent Application 2,167,662A to Dick discloses a matrix implantdevice in the form of a solid cylinder. The matrix is formed from ahydrophobic polymer such as polypropylene, polyethylene, polyvinylchloride, ethylvinyl acetate, polystyrene and polymethacrylate, as wellas glycerol esters of the glycerol palmitostearate, glycerol stearateand glycerol behenate type.

U.S. Pat. No. 3,948,254 to Zaffaroni discloses a hybrid devicecomprising a solid matrix drug reservoir encapsulated in a microporousmembrane, where the membrane pores are filled with a carrier material.

UK Patent Application 2,154,138A to Roche discloses a hybridsubcutaneous implant using silicone rubber. The device is formed as asubstantially hollow cylinder of the silicone rubber, with a coreconsisting of active ingredients dispersed in a biocompatible,biosoluble polymer which dissolves within days of implantation. Thebiocompatible, biosoluble polymer is a mixture of high molecular weightpolyethylene glycol (PEG) and low molecular weight PEG, for example, PEG3,000-10,000 with PEG 200-600.

U.S. Pat. No. 5,035,891 to Runkel discloses a subcutaneous implant madeby formulating compressed pellets containing a biologically activecompound, a solubilizing agent, a solid, hydrophilic, non-toxic polymersufficient to cause swelling by osmotic pressure after implantation,followed by wrapping the pellet(s) in a rate-controlling membrane whichis permeable to the biologically active compound but is impermeable tothe solubilizing agent. The implants so obtained are particularlyadvantageous in a number of respects:

The invention is illustrated in more detail by the followingnon-limiting example:

Example 1

USP testosterone (50-90 mg) and USP anastrozole (4-12 mg) are mixed witha carrier such as stearic acid (0-4 mg). The mixed ingredients aremoulded/compressed in a standard pellet press using 2000 pounds (1 ton)of pressure into cylindrical pellets 3.1 mm diameter.

The individual testosterone/anastrozole pellets are then placed intosealed glass ampoules or standard pharmaceutical ‘peel packs.’ They arethen sterilized using gamma radiation or autoclaved at 121° C. for 40minutes, steam generator pressure 20-25 psi, autoclave jacket pressure15-25. Release rate also appears to be independent of compressionpressure.

Each sterile implant is supplied in a sealed glass ampoule or standardpharmaceutical peel pack. Do not store above 25° C. Store in theoriginal package.

Clinical Data

Efficacy and Safety of subcutaneous anastrozole/testosterone combinationin the elevation of testosterone levels and the prevention of theconversion of testosterone to estradiol is illustrated by the followingcase presentations:

-   -   1. 315 pound, 58 year old male patient previously treated with        subcutaneous testosterone replacement therapy (TRT) that        presented with an extremely elevated estradiol 8 days following        implantation with testosterone pellets (123 pg/mL, optimal range        <30 for males). Two weeks following testosterone pellet        implantation, two 60 mg testosterone/6 mg anastrozole pellets        were implanted into the subcutaneous tissue. One week following        implantation of the combination pellets, estradiol measured <30        pg/mL. Testosterone measured 1341 ng/dL. This was confirmed at        day 13. Estradiol remained optimal, <30 pg/mL and testosterone        measured 1269 ng/dL.    -   2. 67 year old, 214-pound male treated with subcutaneous TRT        with pellet implants presented with an elevated estradiol prior        to re-implantation (54 pg/mL). At the time of testosterone        pellet implantation, one testosterone 60 mg/anastrozole 6 mg        pellet was implanted with 14, 100 mg testosterone pellet        implants. Follow up serum levels at one month revealed a        therapeutic testosterone levels (842 ng/dL) and estradiol <30        pg·mL. FU serum estradiol level at 2½ months was 45 pg/mL,        within range for males (0-54). <30 pg/mL is felt to be optimal.        Follow up estradiol at week 15 was <30 pg/mL. Next insert, two        testosterone/anastrozole pellet implants will be placed.    -   3. 55 year old, 63 inch, 135 pound female with a history of        invasive breast cancer was treated for symptoms of hormone        deficiency with one testosterone 60 mg/anastrozole 6 mg pellet        implant in addition to a 55 mg testosterone pellet. Symptoms of        androgen/hormone deficiency were relieved and the patient had no        side effects from therapy. Ultra-sensitive estradiol measured <7        pg/mL at week 6. Testosterone measured 369 ng/dL. Follow up        estradiol at week ten remained low (10 pg/mL) despite a        therapeutic testosterone level of 139.6 ng/dL. A second        testosterone/anastrozole insert was performed 12 weeks later.        Follow up estradiol measures 10 pg/mL (optimal) with a        therapeutic testosterone level of 305 ng/dL, consistent with        previous results.    -   4. 50 year old, 71 inch, 210 pound female with a history of        metastatic breast cancer, currently on chemotherapy, treated        with one testosterone 60 mg/anastrozole 6 mg pellet implant in        addition to a 100 mg testosterone pellet implant. Estradiol at        day 18 measured <30 pg/mL. Patient noted significant improvement        in bone pain from metastatic disease. An additional testosterone        60 mg/anastrozole 6 mg pellet implant was placed 5 weeks after        initial insert. Patient experienced further reduction of bone        pain. Follow up estradiol remained <30 pg/mL.    -   5. 50 year old, 62 inch, 146 pound female with a history of        invasive breast cancer, was treated with one testosterone 60        mg/anastrozole 6 mg pellet implant in addition to a 55 mg        testosterone pellet implant. Serum estradiol at day 7 measured        <30 pg/mL.    -   6. 57 year old, 68 inch, 192 pound female with a history of        invasive breast cancer, was treated with one testosterone 60        mg/anastrozole 6 mg pellet implant in addition to a 75 mg        testosterone pellet. Serum estradiol at day 13 measured <30        mg/mL. Testosterone measured 165 ng/dL.    -   7. 58 year old, 64 inch, 160 pound female with a history of        breast cancer was treated with one testosterone 60        mg/anastrozole 6 mg pellet implant in addition to an 80 mg        testosterone pellet. Serum estradiol at day 24 measured <30        pg/mL and testosterone measured 169 ng/dL.    -   8. 73 year old, 62.5 inch, 170 pound female with a history of        non-invasive (DCIS), bilateral breast cancer, was treated with        one testosterone 60 mg/anastrozole 6 mg pellet implant in        addition to a 100 mg testosterone pellet implant. Serum        estradiol at day 13 measured <30 pg/mL and testosterone measured        290 ng/dL.    -   9. 56 year old, 65.5 inch, 220 pound female with a history of        breast cancer, was treated with one testosterone 60        mg/anastrozole 6 mg pellet implant in addition to a 100 mg        testosterone pellet implant. Estradiol at day 25 measured <30        pg/mL and testosterone measured 247 ng/dL.    -   10. 53 year old, 59 inch, 183 pound female with a history of        invasive breast cancer treated with chemotherapy was treated        with one testosterone 60 mg/anastrozole 6 mg pellet implant in        addition to a 100 mg testosterone pellet implant. Serum        estradiol at day 7 measured <30 pg/mL, estrone <10 pg/mL and        testosterone measured 220 ng/dL. Previously she had been unable        to tolerate ‘low dose’ (0.5 mg twice weekly) oral anastrozole,        complaining of severe hot flashes, night sweats “all through the        night”, and headaches. She had discontinued the oral        anastrozole. She experienced no side effects with the        subcutaneous anastrozole with testosterone pellet implant.    -   11. 54 year old, 67 inch, 145 pound female with a history of        non-invasive breast cancer (DCIS), was treated with one        testosterone 60 mg/anastrozole 6 mg pellet implant in addition        to a 55 mg testosterone pellet implant. Serum ‘sensitive’        estradiol at day 7 measured 25 pg/mL. Serum estrone also        remained low, 22 pg/mL.    -   12. 64 year old, 144 pound female with a history of breast        cancer, was treated with one testosterone 60 mg/anastrozole 6 mg        pellet implant in addition to a 55 mg testosterone pellet        implant. Serum estradiol measured <10 pg/mL and testosterone        measured 313.9 ng/dL at week one.    -   13. 78 year old, 140 pound female with a history of breast        cancer, was treated with one testosterone 60 mg/anastrozole 6 mg        pellet implant in addition to a 55 mg testosterone pellet        implant. Day 9, serum estrone measured <10 pg/mL, estriol <0.10        and testosterone 300 ng/dL.    -   14. 45 year old, 66 inch, 135 pound female with a history of        breast cancer, was treated with one testosterone 60        mg/anastrozole 6 mg pellet implant in addition to a 55 mg        testosterone pellet implant. Serum estradiol at week one        measured <30 pg/mL, estrone <10 pg/mL with a therapeutic        testosterone of 136 ng/dL.    -   15. 51 year old, 154 pound female with a history of metastatic        breast cancer, was treated with one testosterone 60        mg/anastrozole 6 mg pellet implant in addition to a 100 mg        testosterone pellet implant. Day 18, serum estradiol measured        <10 ng/dL, total estrogens <1.0 ng/dL and testosterone 404        ng/dL.    -   16. 48 year old, 66 inch, 155 pound female with a history of        invasive breast cancer, was treated with one testosterone 60        mg/anastrozole 6 mg pellet implant in addition to a 100 mg        testosterone pellet implant. Serum estradiol at week one        measured <30 pg/mL with a therapeutic testosterone of 232 ng/dL.    -   17. 61 year old, 64 inch, 160 pound female with a history of        invasive breast cancer 15 years prior treated with chemotherapy        and tamoxifen treated with one testosterone 60 mg/anastrozole 6        mg pellet implant in addition to a 75 mg testosterone pellet        implant. Serum estradiol at week one measured <30 pg/mL, Estrone        was 15 pg/mL (optimal) with a therapeutic testosterone of 191        ng/dL.    -   18. 67 year old, 67 inch, 170 pound female with a history of        DCIS, ductal carcinoma in situ (non invasive breast cancer),        treated with lumpectomy and radiation therapy. The patient with        one testosterone 60 mg/anastrozole 6 mg pellet implant in        addition to a 65 mg testosterone pellet implant. Serum estradiol        measured <10 pg/mL, Estrone 4.3 pg/mL (3-32 pg/mL post men),        with a therapeutic testosterone level of 453 ng/dL.    -   19. 47 year old, 210 pound female with a history of breast        cancer, was treated with one testosterone 60 mg/anastrozole 6 mg        pellet implant in addition to a 100 mg testosterone pellet        implant. Day 12, serum estradiol measured 41 pg/mL (not        considered elevated, but slightly above post menopausal levels)        with a therapeutic testosterone of 338 ng/dL. Patient felt        great. Estradiol was remeasured at week 4, and testosterone was        460 ng/dL, and estradiol was <30 pg/mL, FSH 50.2.

While the invention has been illustrated by several expressions ofseveral embodiments, and enablements, and applications, thereof, theinvention is defined by the appended claims and is not limited to thespecific examples. Numerous variations, modifications, and substitutionsare possible without departing from the scope of the invention asdefined in the appended claims. It will be understood that the foregoingdescription is provided by way of example, and that other modificationsmay occur to those skilled in the art without departing from the scopeand spirit of the appended Claims.

What is claimed is:
 1. An implant comprising a mixture of an amount oftestosterone or an ester thereof and an amount of aromatase inhibitor ina weight ratio of testosterone or an ester thereof to aromataseinhibitor of 5:1 to 30:1, wherein the mixture forms a single implantwith continuous delivery and zero order release of the testosterone orester thereof and the aromatase inhibitor for a period of at least 30days.
 2. The implant of claim 1, wherein the aromatase inhibitor isselected from the group consisting of anastrozole, letrozole, andexemestane.
 3. The implant of claim 1, further comprising an amount of apharmaceutically acceptable excipient.
 4. The implant of claim 1,wherein the implant is a sustained release, subcutaneous implant.
 5. Theimplant of claim 1, wherein the amount of testosterone is about 30 mg to200 mg and the amount of aromatase inhibitor is about 1 mg to 90 mg. 6.The implant of claim 1, wherein the amount of testosterone or an esterthereof and the amount of aromatase inhibitor is a weight ratio oftestosterone or an ester thereof to aromatase inhibitor of about 15:1.7. The implant of claim 1, wherein the amount of testosterone or anester thereof and the amount of aromatase inhibitor are released intothe blood at a controlled rate.
 8. The implant of claim 3, wherein theexcipient comprises a lubricant, a binder, or a combination thereof. 9.The implant of claim 1, wherein the amount of aromatase inhibitorprovides less than 54 pg/ml estradiol level in the blood.
 10. Theimplant of claim 3, wherein the amount of excipient is less than about5% by weight based on composition weight.
 11. The implant of claim 1,wherein the aromatase inhibitor comprises anastrozole.
 12. The implantof claim 1, wherein the amount of testosterone or an ester thereof isabout 60 mg and the amount of aromatase inhibitor is about 4 mg.
 13. Animplant comprising a mixture of an amount of testosterone or an esterthereof and an amount of aromatase inhibitor in a weight ratio oftestosterone or an ester thereof to aromatase inhibitor of about 5:1 to30:1, wherein the amount of testosterone or an ester thereof and theamount of aromatase inhibitor are continuously delivered at a zero orderrelease for a period of at least 30 days, and wherein the amount ofaromatase inhibitor prevents formation of estradiol from thetestosterone and provides less than 54 pg/ml estradiol level in theblood.
 14. The implant of claim 13, wherein the implant is a sustainedrelease, subcutaneous implant.
 15. The implant of claim 13, furthercomprising a pharmaceutically acceptable excipient.
 16. The implant ofclaim 13, wherein the aromatase inhibitor is selected from the groupconsisting of anastrozole, letrozole, and exemestane.
 17. The implant ofclaim 13, wherein the amount of testosterone or an ester thereof isabout 30 mg to 200 mg and the amount of aromatase inhibitor is about 1mg to 90 mg.
 18. The implant of claim 13, wherein the weight ratio oftestosterone or an ester thereof to aromatase inhibitor is about 15:1.19. The implant of claim 1, wherein the aromatase inhibitor comprisesletrozole.